Carbohydrate Strengthens the Immunotherapeutic Effect of Small-Molecule PD-L1 Inhibitors

  • J Med Chem. 2023 Jun 8;66(11):7179-7204. doi: 10.1021/acs.jmedchem.2c01347.
Qian Dong  1  2  3 ,  Mengya Tong  2 ,  Xiaolu Yu  2 ,  Lei Wang  2 ,  Jiwei Ao  2 ,  Dongliang Guan  2 ,  Yubo Tang  2 ,  Junjie Liu  2 ,  Li Long  2 ,  Yongliang Tong  2 ,  Shanhua Fang  2 ,  Hu Zhou  2  3 ,  Yongzhuo Huang  2  3 ,  Likun Gong  2  3 ,  Liguang Lou  2  3 ,  Wei Huang  1  2  3
Affiliations
  • 1. School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. University of Chinese Academy of Sciences, Beijing 100049, China.
PMID: 37226718 DOI: 10.1021/acs.jmedchem.2c01347
Abstract

PD-1/PD-L1 checkpoint blockade has demonstrated great success in Cancer Immunotherapy. Small-molecule PD-L1 inhibitors also attract significant research interests but remain challenging in the efficacy and safety. Carbohydrate moiety and carbohydrate-binding proteins (lectins) play important roles in immune modulation including antigen recognition and presenting. Herein, we reported a novel strategy to strengthen the immunotherapeutic effect of small-molecule PD-L1 inhibitors by introducing sugar motifs, which may utilize the carbohydrate-mediated immune enhancement for Cancer treatment. The data revealed that glycoside compounds containing mannose or N-acetylglucosamine exhibited the best results in IFN-γ secretion. Moreover, compared to the nonglycosylated compounds, glycosides C3 and C15 demonstrated significant lower cytotoxicity and effective in vivo antitumor potency in the CT26 and melanoma B16-F10 tumor models with good tolerance. Notably, tumor-infiltrating lymphocyte (TIL) analysis validated increased CD3+, CD4+, CD8+, and granzyme B+ T cells after glycoside treatments. This work presents a new concept to improve the immunotherapy.